The long-term goal of this research is to understand and thus manipulate the antigen-specific interactions between the alpha/beta T cell antigen receptor (TCR) and its peptide/MHC ligand. We have chosen to study the TCR/ligand interactions in the mouse minor histocompatibility (H) antigen models. Using novel methods developed in our laboratory we have isolated five different polymorphic H antigen genes (H3a, H13, H28,H47 and H60) that elicit potent CD8 T cell responses when appropriate host mouse strains are immunized with donor cells differing at one or more of these H loci. We have also developed new methods for identifying CD4 T cell stimulating antigen genes which up until now have remained virtually unknown because of extraordinary technical difficulties. Here we propose to identify currently unknown CD4 T cell stimulating H antigen genes to test the hypothesis is that these may be different from those that elicit CD8 T cell responses and could represent an unique sub-set of polymorphic proteins. We will use these new H antigens together with the known H antigens to further test the hypothesis that CD4 and CD8 T cell responses can be elicited to the same H antigens regardless of the MHC haplotype. Finally, we have determined that a hierarchy exists among the CD8 T cells in response to multiple H epitopes. We will determine whether this epitope hierarchy is due to differences in direct or indirect presentation of donor H peptide/MHC or the host T cell repertoire. We expect the findings to reveal new insights into the nature of endogenous peptides presented by MHC class II and MHC class I molecules in normal cells as well as fundamental issues in transplantation immunology.